Targeted therapies have the ability to specifically interact with and block proliferation of cancer cells by interfering with targeted gene products required for the malignant phenotype. Unlike conventional cancer chemotherapies, targeted therapies do not harm normal cells of the body. This class of therapeutic has been met with considerable clinical success indicating that there is a great need for new targeted therapies that block progression of other types of cancer for which no targeted therapy exists. We hypothesize that all hematopoietic cells (normal and cancerous) express genes responsible for maintaining the blood lineage and blood cancer phenotypes, and that the products of these genes can be exploited by new targeted therapies. Identification of these hematopoieitc-specific lethal genes would allow for the development of novel targeted therapies for combating diverse blood cancers, and for developing tissue-specific, targeted conditioning regimens for hematopoietic stem cell transplantation with greatly reduced morbidity and mortality. We tested this hypothesis in the course of Phase I studies, and demonstrated that pooled shRNA genetic viability screens could be successfully used to identify novel lethality drug targets specific for hematopoietic cancer cell types. We also identified small molecule agents that exhibited hematopoietic-specificity closely correlating lethality profiles of the shRNAs identified in genetic screens. In order to translate this researches into the future development of novel classes of targeted therapies, we propose in the Phase II studies to concurrently apply genome-wide RNAi-based genetic screening and small molecule library high-throughput (HT) screens to identify lethality genes and cytotoxic small molecules specific for members of a diverse panel of hematopoetic cell lines. The hematopoieitc-specific lethal shRNAs, and small molecules targeting lethality genes will be further validated using a wide panel of hematopoietic and non-hematopoietic cell lines and normal PBMC. Similar toxicity/lethality profiles will allow us to prioritize cytotoxic compounds based on their mechanism of action and simultaneously identify their specific drug target(s). These studies will be extended to the lead compounds for targeted therapy of hematological cancers in Phase III of the project in a joint drug development project between Cellecta and Tartis, Inc.